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81.
Johanna Christina Czeschik Ute Hehr Britta Hartmann Hermann-Josef Lüdecke Thorsten Rosenbaum Bernd Schweiger Dagmar Wieczorek 《European journal of medical genetics》2013,56(12):689-694
Walker–Warburg syndrome (WWS) is a severe muscular dystrophy with eye and brain malformations. On a molecular level, WWS is a disorder of the O-linked glycosylation of α-dystroglycan and therefore referred to as one of the dystroglycanopathies. The disease family of muscular dystrophy–dystroglycanopathy (MDDG) contains a spectrum of severe to mild disorders, designated as MDDG type A to C. WWS, as the most severe manifestation, corresponds to MDDG type A. Defects in the genes POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GTDC2, G3GALNT2, GMPPB, B3GNT1, TMEM5 and COL4A1 and ISPD have been described as causal for several types of MDDG including WWS, but can only be confirmed in about 60–70% of the clinically diagnosed individuals. The proteins encoded by these genes are involved in the posttranslational modification of α-dystroglycan. Mutations in POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GMPPB, TMEM5 and COL4A1 and ISPD lead to a wide spectrum of phenotypes of congenital muscular dystrophies with or without eye and brain abnormalities. Patients with WWS frequently demonstrate a complete lack of psychomotor development, severe eye malformations, cobblestone lissencephaly and a hypoplastic cerebellum and brainstem, seizures, hydrocephalus and poor prognosis. Here, we present a boy with WWS who showed compound heterozygous changes in ISPD and discuss the clinical and radiological phenotype and the molecular genetic findings, including a novel pathogenic mutation in ISPD. 相似文献
82.
Pawel Buczkowicz Ute Bartels Eric Bouffet Oren Becher Cynthia Hawkins 《Acta neuropathologica》2014,128(4):573-581
Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II–IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III–IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II–IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas. 相似文献
83.
Ebner F Tepest R Dani I Pfeiffer U Schulze TG Rietschel M Maier W Träber F Block W Schild HH Wagner M Steinmetz H Gaebel W Honer WG Schneider-Axmann T Falkai P 《Schizophrenia Research》2008,104(1-3):71-78
BACKGROUND: Hippocampal volume reduction is a well replicated finding in schizophrenia. Evidence indicates a contribution of genetic and environmental factors, especially the influence of obstetric complications to this volume reduction. The aim of this study was to compare hippocampal volume of schizophrenic patients as well as and their relatives with control subjects and to quantify the additional contribution of obstetric complications. METHODS: T1 weighted MRI brain scans of 50 schizophrenic patients, 88 first-degree relatives and 53 healthy control subjects were used to perform volumetric measurements on the left and right hippocampus. A set of clinical measures including obstetric complications were recorded for all family members. RESULTS: Numerically our measurements revealed a hippocampal volume reduction in schizophrenic patients (left: - 14%, right: - 15%) and, although less pronounced, in their unaffected relatives (left: - 6%, right: - 10%). Noted differences in hippocampal volume between schizophrenic patients and controls were only significant for the left side. Hippocampal volumes of patients and their relatives with obstetric complications were reduced bilaterally. CONCLUSIONS: Hippocampal volume reduction is present in schizophrenic patients and their first-degree relatives, suggesting an influence of genetic factors.. In addition, however, obstetric complications have also been shown to play a major role. 相似文献
84.
Test‐retest reliability of the default mode network in a multi‐centric fMRI study of healthy elderly: Effects of data‐driven physiological noise correction techniques 下载免费PDF全文
Rocco Marchitelli Ludovico Minati Moira Marizzoni Beatriz Bosch David Bartrés‐Faz Bernhard W. Müller Jens Wiltfang Ute Fiedler Luca Roccatagliata Agnese Picco Flavio Nobili Oliver Blin Stephanie Bombois Renaud Lopes Régis Bordet Julien Sein Jean‐Philippe Ranjeva Mira Didic Hélène Gros‐Dagnac Pierre Payoux Giada Zoccatelli Franco Alessandrini Alberto Beltramello Núria Bargalló Antonio Ferretti Massimo Caulo Marco Aiello Carlo Cavaliere Andrea Soricelli Lucilla Parnetti Roberto Tarducci Piero Floridi Magda Tsolaki Manos Constantinidis Antonios Drevelegas Paolo Maria Rossini Camillo Marra Peter Schönknecht Tilman Hensch Karl‐Titus Hoffmann Joost P. Kuijer Pieter Jelle Visser Frederik Barkhof Jorge Jovicich 《Human brain mapping》2016,37(6):2114-2132
Understanding how to reduce the influence of physiological noise in resting state fMRI data is important for the interpretation of functional brain connectivity. Limited data is currently available to assess the performance of physiological noise correction techniques, in particular when evaluating longitudinal changes in the default mode network (DMN) of healthy elderly participants. In this 3T harmonized multisite fMRI study, we investigated how different retrospective physiological noise correction (rPNC) methods influence the within‐site test‐retest reliability and the across‐site reproducibility consistency of DMN‐derived measurements across 13 MRI sites. Elderly participants were scanned twice at least a week apart (five participants per site). The rPNC methods were: none (NPC), Tissue‐based regression, PESTICA and FSL‐FIX. The DMN at the single subject level was robustly identified using ICA methods in all rPNC conditions. The methods significantly affected the mean z‐scores and, albeit less markedly, the cluster‐size in the DMN; in particular, FSL‐FIX tended to increase the DMN z‐scores compared to others. Within‐site test‐retest reliability was consistent across sites, with no differences across rPNC methods. The absolute percent errors were in the range of 5–11% for DMN z‐scores and cluster‐size reliability. DMN pattern overlap was in the range 60–65%. In particular, no rPNC method showed a significant reliability improvement relative to NPC. However, FSL‐FIX and Tissue‐based physiological correction methods showed both similar and significant improvements of reproducibility consistency across the consortium (ICC = 0.67) for the DMN z‐scores relative to NPC. Overall these findings support the use of rPNC methods like tissue‐based or FSL‐FIX to characterize multisite longitudinal changes of intrinsic functional connectivity. Hum Brain Mapp 37:2114–2132, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
85.
Right heart function in impaired left ventricular diastolic function: 2D speckle tracking echocardiography–based and Doppler tissue imaging–based analysis of right atrial and ventricular function 下载免费PDF全文
Anna Brand MD Marny Bathe Sabine Oertelt‐Prigione MScPH Ute Seeland MD Mirjam Rücke MSc Vera Regitz‐Zagrosek MD Karl Stangl MD Fabian Knebel MD Verena Stangl MD Henryk Dreger MD 《Echocardiography (Mount Kisco, N.Y.)》2018,35(1):47-55
Aim
The aim of our study was to describe right atrial (RA) and right ventricular (RV) function, assessed by Doppler tissue imaging and 2D speckle tracking echocardiography (2DSTE), in women with signs of early impaired left ventricular diastolic function (DD).Methods and Results
In a cross‐sectional trial, standard parameters of diastolic and right heart function were investigated in 438 women of the Berlin Female Risk Evaluation (BEFRI) study. In a subset of women, average peak systolic RA strain (RAS), as well as the average peak systolic RV strain of the free wall (RVS free wall) and of all RV segments (average RV strain; RVS Avg), was analyzed using 2DSTE. Compared to women with normal diastolic function (DD0), RAS, RVS free wall and RVS Avg were significantly reduced in DD (43.1% ± 11.9%, ?26.7% ± 5.6%, and ?23.3% ± 3.5% in DD0; vs 35.1% ± 10.4%, ?23.9% ± 5.5%, and ?20.6% ± 3.8% in DD; P < .01). Peak RV myocardial velocity (RV‐IVV) and acceleration during isovolumetric contraction (RV‐IVA) were markedly higher in DD (15.0 ± 3.9 cm/s and 3.1 ± 1.0 m/s² in DD vs 11.9 ± 3.2 cm/s and 2.8 ± 0.8 m/s² in DD0; P < .05). RAS and RV‐IVV were significantly associated with DD after adjustment to age, BMI, and left atrial strain in multivariate regression analysis.Conclusion
Systolic right heart function is significantly altered in DD. DTI as well as 2DSTE constitute sensitive echocardiographic tools that enable the diagnosis of impaired right heart mechanics in early‐staged DD. 相似文献86.
Laurel Young Amel Katrib Carolyn Cuello Ute Vollmer‐Conna James V. Bertouch Peter J. Roberts‐Thomson Michael J. Ahern Malcolm D. Smith Peter P. Youssef 《Arthritis \u0026amp; Rheumatology》2001,44(2):343-350
Objective
To investigate the effects of intraarticular glucocorticoid treatment on macrophage infiltration, the expression of the chemokines monocyte chemoattractant protein 1 (MCP‐1) and macrophage inflammatory protein 1α (MIP‐1α), and the expression of matrix metalloproteinases 1 and 3 (MMPs 1 and 3) and their inhibitors, the tissue inhibitors of metalloproteinases 1 and 2 (TIMPs 1 and 2), in osteoarthritis (OA) synovial membranes.Methods
Forty patients underwent arthroscopic biopsy before and 1 month after intraarticular injection of glucocorticoids. Twenty‐one patients received 120 mg of methylprednisolone acetate (Depo‐Medrol; Upjohn, Kalamazoo, MI), and 20 patients received placebo (1 patient received placebo in 1 knee and methylprednisolone acetate in the other). Immunoperoxidase staining for the expression of CD68, MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 was performed, and the immunostaining was quantified by color video image analysis.Results
CD68, MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 immunostaining was observed in all synovial membranes. Intraarticular glucocorticoid treatment was associated with a small (30%) but statistically significant (P = 0.048) reduction in CD68+ macrophage staining in the synovial lining layer, but there was no change in the CD68 expression in the synovial sublining layer. No significant differences were observed for MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 immunostaining in the synovial lining or sublining layers.Conclusion
Intraarticular glucocorticoids may reduce CD68+ macrophage infiltration into the synovial lining layer, but not the expression of MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 in the synovial membrane, in patients with OA.87.
Steffen Moritz Florian Scheu Christina Andreou Ute Pfueller Matthias Weisbrod Daniela Roesch-Ely 《Cognitive neuropsychiatry》2016,21(2):91-106
Introduction. A liberal acceptance (LA) threshold for hypotheses has been put forward to explain the well-replicated “jumping to conclusions” (JTC) bias in psychosis, particularly in patients with paranoid symptoms. According to this account, schizophrenia patients rest their decisions on lower subjective probability estimates. The initial formulation of the LA account also predicts an absence of the JTC bias under high task ambiguity (i.e., if more than one response option surpasses the subjective acceptance threshold).Methods. Schizophrenia patients (n?=?62) with current or former delusions and healthy controls (n?=?30) were compared on six scenarios of a variant of the beads task paradigm. Decision-making was assessed under low and high task ambiguity. Along with decision judgments (optional), participants were required to provide probability estimates for each option in order to determine decision thresholds (i.e., the probability the individual deems sufficient for a decision).Results. In line with the LA account, schizophrenia patients showed a lowered decision threshold compared to controls (82% vs. 93%) which predicted both more errors and less draws to decisions. Group differences on thresholds were comparable across conditions. At the same time, patients did not show hasty decision-making, reflecting overall lowered probability estimates in patients.Conclusions. Results confirm core predictions derived from the LA account. Our results may (partly) explain why hasty decision-making is sometimes aggravated and sometimes abolished in psychosis. The proneness to make risky decisions may contribute to the pathogenesis of psychosis. A revised LA account is put forward. 相似文献
88.
c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis 总被引:1,自引:0,他引:1 下载免费PDF全文
Gebhardt C Breitenbach U Richter KH Fürstenberger G Mauch C Angel P Hess J 《The American journal of pathology》2005,167(1):243-253
Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. It has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and anti-tumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer. 相似文献
89.
Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling 总被引:2,自引:0,他引:2
Farhat K Riekenberg S Heine H Debarry J Lang R Mages J Buwitt-Beckmann U Röschmann K Jung G Wiesmüller KH Ulmer AJ 《Journal of leukocyte biology》2008,83(3):692-701
TLR are primary triggers of the innate immune system by recognizing various microorganisms through conserved pathogen-associated molecular patterns. TLR2 is the receptor for a functional recognition of bacterial lipopeptides (LP) and is up-regulated during various disorders such as chronic obstructive pulmonary disease and sepsis. This receptor is unique in its ability to form heteromers with TLR1 or TLR6 to mediate intracellular signaling. According to the fatty acid pattern as well as the assembling of the polypeptide tail, LP can signal through TLR2 in a TLR1- or TLR6-dependent manner. There are also di- and triacylated LP, which stimulate TLR1-deficient cells and TLR6-deficient cells. In this study, we investigated whether heterodimerization evolutionarily developed to broaden the ligand spectrum or to induce different immune responses. We analyzed the signal transduction pathways activated through the different TLR2 dimers using the three LP, palmitic acid (Pam)octanoic acid (Oct)(2)C-(VPGVG)(4)VPGKG, fibroblast-stimulating LP-1, and Pam(2)C-SK(4). Dominant-negative forms of signaling molecules, immunoblotting of MAPK, as well as microarray analysis indicate that all dimers use the same signaling cascade, leading to an identical pattern of gene activation. We conclude that heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of LP present in various pathogens. Thus, although mycoplasma and Gram-positive and Gram-negative bacteria may activate different TLR2 dimers, the development of different signal pathways in response to different LP does not seem to be of vital significance for the innate defense system. 相似文献
90.
Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). 总被引:2,自引:0,他引:2
Ute Moog Eric E J Smeets Kees E P van Roozendaal Sam Schoenmakers Jos Herbergs Anneke M J Schoonbrood-Lenssen Connie T R M Schrander-Stumpel 《European journal of paediatric neurology》2003,7(1):5-12
Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed. 相似文献